Increasing evidences have shown that miR-449a is involved in the regulation of tumorigenesis and autophagy, and autophagy plays important roles in the malignancy of T-cell lymphoma. However, it is still unknown whether miR-449a is associated with autophagy in regulating the malignancy of T-cell lymphoma. In this study, we for the first time demonstrated that miR-449a enhanced apoptosis of T-cell lymphoma cells via decreasing autophagy level. Moreover, the study of the corresponding mechanism by which miR-449a attenuated autophagy showed that miR-449a downregulated autophagy related 4B (ATG4B) expression, which subsequently reduced the autophagy level of T-cell lymphoma cells. Mechanistically, miR-449a decreased ATG4B protein level by binding to its mRNA 3'UTR and thus reducing its mRNA stability. In addition, nude mice experiments showed that miR-449a remarkably exhibited anti-lymphoma characteristics in vivo. In conclusion, our results demonstrated that the “miR-449a/ATG4B/autophagy” pathway played a vital role in the malignancy of T-cell lymphoma, suggesting that this pathway may be a novel target for the treatment of T-cell lymphoma.